The present invention is directed toward retinoids, and more particularly to a method of reducing the toxicity of retinoids and modified retinoids having reduced toxicity.
All trans-retinol, the major circulating form of vitamin A, is converted in the body to retinaldehyde and finally to all-trans-retinoic acid (atRA) (Blomhoff et al., 1992, Annu. Rev. Nutr. 12:37-57). atRA serves as the active form of vitamin A in cellular differentiation and growth, and embryonic development, whereas the aldehyde serves as the active form in the visual cycle (Palczewski and Saari, 1997, Curr. Opin. Neurobiol. 7:500-504). It is also believed that atRA serves as the active form in the reproductive functions of vitamin A (Clagett-Dame and DeLuca, 2002, Annu. Rev. Nutr. 22:347-381).
atRA, in addition to being a functionally active form of vitamin A, is also the parent of a family of drugs used both topically and orally for the treatment of a number of skin conditions (Ellis and Krach, 2001, J. Am. Acad. Dermatol. 45:S150-S157; Zouboulis, 2001, Skin Pharmacol. 14:303-315). Furthermore, it and some of its isomers are being considered as chemo-preventive agents, for example in epithelial tumors, and may also serve as a therapy for certain types of leukemias (Fenaux and Degos, 2000, Leukemia 14:1371-1377). atRA is believed to function by binding to a series of retinoic acid receptor subtypes, α, β and γ, that also vary in sequence due to differences in promoter usage and splicing (Chambon, 1996, FASEB J. 10:940-954). atRA and its analogs are believed to act through a nuclear receptor (RAR) to activate or suppress target genes responsible for its actions (Clagett-Dame and Plum, 1997, Crit. Rev. Euk. Gene Exp. 7:299-342; McCaffery and Dräger, 2000, Cytokine Growth Factor Rev. 11:233-249). atRA is formed in regulated quantities because it is extremely potent and readily activates the retinoic acid receptors (Duester, 2000, Eur. J. Biochem. 267:4315-4324). atRA is also rapidly metabolized so that its lifetime is relatively short (Roberts and DeLuca, 1967, Biochem. J. 102:600-605).
Because it is immediately active, pharmacological amounts of orally administered RA isomers have very serious side effects (Armstrong et al., 1994, in The Retinoids, pp. 545-572; DiGiovanna, 2001, J. Am. Acad. Dermatol. 45:S176-S182). Among them are frank toxicity resulting in weight loss, inanition, eye encrustation, and bone loss. Common side effects with pharmacological use of 13-cis RA (isotretinoin), a major orally administered form of RA, includes mucocutaneous toxicity and hyperlipidemia (Ellis and Krach, 2001, J. Am. Acad. Dermatol. 45:5150-5157). An even more serious problem is that RA isomers have significant teratogenic activity in pregnant mammals (Collins and Mao, 1999, Ann. Rev. Pharmacol. 39:399-430; Nau, 2001, J. Am. Acad. Dermatol. 45:S183-S187). These side effects have been a serious limitation to the use of oral retinoids in therapy. Although topically applied retinoids carry little teratogenic liability (Nau, 1993, Skin Pharmacol. 6:535-544; Buchan et al., 1994, J. Am. Acad. Dermatol. 30:428-434; Chen et al., 1997, J. Clin. Pharmacol. 37:279-284), there are other toxicities associated with this route of administration that limit their use including skin irritation (Orfanos et al., 1997, Drugs 53:358-388). A major reason for both oral and topical toxicity is that the retinoids are totally and immediately available upon administration. A process whereby a retinoid can be made available in vivo more slowly and more continuously would avoid peaks and valleys in the availability of the retinoid thereby providing an effective in vivo level of the compound over a more prolonged period of time and also avoiding or substantially reducing the toxicities that often result from the sudden availability of excessive amounts of the substance.